Ionic polymers as toxin-binding agents

Abstract

A method for treating pathogenic toxins in a mammal, such as a human, comprising treating the mammal with a therapeutically effective amount of a polymer comprising a cationic group attached to the polymer backbone. The polymer can be a homopolymer or a copolymer. In one embodiment, the polymer is a copolymer comprising a monomer having a pendant ammonium group and a hydrophobic monomer.

What is claimed is:  
     
       1. A method for inhibiting a pathogenic toxin in a mammal, comprising the step of orally administering to the mammal a therapeutically effective amount of a polymer characterized by a repeat unit of comprising a plurality of Formula I,                    
       wherein R is a hydrogen atom or a methyl or ethyl group; X is a covalent bond, a carbonyl group or a CH 2  group; Y is an oxygen atom or an NH or CH 2  group; Z is an aliphatic spacer group; R 1 , R 2  and R 3  are each, independently, a hydrogen atom, a normal or branched, substituted or unsubstituted C 1 -C 24 -alkyl group, aryl or arylalkyl group; and m and n are each, independently, 1 or 0; or —N + (R 1 )(R 2 )(R 3 ) is a heteroaryl group; and A −  is a pharmaceutically acceptable anion; or a free base thereof. 
     
     
       2. The method of claim  1  wherein Z is a normal or branched C 2 -C 24 -alkylene group or a C 2 -C 24 -alkylene group interrupted at one or more points by a heteroatom. 
     
     
       3. The method of claim  2  wherein the heteroatom is a nitrogen, oxygen or sulfur atom. 
     
     
       4. The method of claim  3  wherein at least one of R 1 , R 2  and R 3  is an aryl group, a benzyl group or a normal or branched, substituted or unsubstituted C 1 -C 24 -alkyl group. 
     
     
       5. The method of claim  3  wherein R 1 , R 2  and R 3  are each hydrogen. 
     
     
       6. The method of claim  1  wherein the polymer is further characterized by a difunctional cross-linking monomer. 
     
     
       7. The method of claim  6  wherein the difunctional cross-linking monomer is selected from the group consisting of diacrylates, triacrylates and tetraacrylates, dimethacrylates, diacrylamides, diallylacrylamide, di(methacrylamides), triallylamine and tetraaleylammonium ion. 
     
     
       8. The method of claim  7  wherein the difunctional cross-linking monomer is selected from the group consisting of ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, butylene glycol dimethacrylate, methylene bis(methacrylamide), ethylene bis(acrylamide), ethylene bis(methacrylamide), ethylidene bis(acrylamide), ethylidene bis(methacrylamide), pentaerythritol tetraacrylate, trimethylolpropane triacrylate, bisphenol A dimethacrylate, bisphenol A diacrylate and divinylbenzene. 
     
     
       9. The method of claim  1  wherein the polymer is crosslinked by a bridging unit selected from the group consisting of straight chain or branched, substituted or unsubstituted alkylene groups, diacylalkylene groups, diacylarene groups and alkylene bis(carbamoyl) groups. 
     
     
       10. The method of claim  9  wherein the bridging units are selected from the group consisting of —(CH 2 ) n —, wherein n is an integer from about 2 to about 20; —CH 2 —CH(OH)—CH 2 —; —C(O)CH 2 CH 2 C(O)—; —CH 2 —CH(OH)—O—(CH 2 ) m —O—CH(OH) —CH 2 —, wherein m is 2 to about 4; —C(O)—(C 6 H 2 (COOH) 2 )—C(O)—; and —C(O)NH(CH 2 ) p NHC(O)—, wherein p is an integer from about 2 to about 20. 
     
     
       11. A method for inhibiting a pathogenic toxin in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a polymer characterized by a repeat unit of the formula                    
       wherein R 1 , R 2  and R 3  are each hydrogen. 
     
     
       12. The method of claim  1  I wherein the polymer is crosslinked by a bridging unit selected from the group consisting of straight chain or branched, substituted or unsubstituted alkylene groups, diacylalkylene groups, diacylarene groups and alkylene bis(carbamoyl) groups. 
     
     
       13. The method of claim  12  wherein the bridging units are selected from the group consisting of —(CH 2 ) n —, wherein n is an integer from about 2 to about 20; —CH 2 —CH(OH)—CH 2 —; —C(O)CH 2 CH 2 C(O)—; —CH 2 —CH(OH)—O—(CH 2 ) m —O—CH(OH) —CH 2 —, wherein m is 2 to about 4; —C(O)—(C 6 H 2 (COOH) 2 )—C(O)—; and —C(O)NH(CH 2 ) p NHC(O)—, wherein p is an integer from about 2 to about 20. 
     
     
       14. The method of claim  13  wherein the bridging units are —CH 2 —CH(OH)—CH 2 —. 
     
     
       15. A method for inhibiting a pathogenic toxin in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a polymer characterized by a first repeat unit of Formula III,                    
       wherein both R 1  and R 2  are hydrogen; and 
       a second repeat unit of Formula III wherein R 1  and R 2  are each, independently, a C 1 -C 24 -alkyl group.  
     
     
       16. The method of claim  15  wherein in the second repeat unit of Formula III, R 1  is a methyl group and R 2  is a linear or branched C 1 -C 18  alkyl group. 
     
     
       17. The method of claim  15  wherein the polymer is cross-linked. 
     
     
       18. The method of claim  11  wherein the polymer is crosslinked by a bridging unit selected from the group consisting of straight chain or branched, substituted or unsubstituted alkylene groups, diacylalkylene groups, diacylarene groups and alkylene bis(carbamoyl) groups. 
     
     
       19. The method of claim  12  wherein the bridging units are selected from the group consisting of —(CH 2 ) n —, wherein n is an integer from about 2 to about 20; —CH 2 —CH(OH)—CH 2 —; —C(O)CH 2 CH 2 C(O)—; —CH 2 —CH(OH)—O—(CH 2 ) m —O—CH(OH) —CH 2 —, wherein m is 2 to about 4; —C(O)—(C 6 H 2 (COOH) 2 )—C(O)—; and —C(O)NH(CH 2 ) p NHC(O)—, wherein p is an integer from about 2 to about 20. 
     
     
       20. The method of claim  19  wherein the polymer is further characterized by a difunctional cross-linking monomer. 
     
     
       21. The method of claim  20  wherein the difunctional cross-linking monomer is selected from the group consisting of diacrylates, triacrylates and tetraacrylates, dimethacrylates, diacrylamides, diallylacrylamide, di(methacrylamides), triallylamine and tetraalylammonium ion. 
     
     
       22. The method of claim  21  wherein the difunctional cross-linking monomer is selected from the group consisting of ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, butylene glycol dimethacrylate, methylene bis(methacrylamide), ethylene bis(acrylamide), ethylene bis(methacrylamide), ethylidene bis(acrylamide), ethylidene bis(methacrylamide), pentaerythritol tetraacrylate, trimethylolpropane triacrylate, bisphenol A dimethacrylate, bisphenol A diacrylate and divinylbenzene. 
     
     
       23. A method for inhibiting a pathogenic toxin in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a cross-linked polymer, wherein said cross-linked polymer comprises first and second polymer strands connected by a linking group, wherein: 
       said first polymer strand is characterized by a repeat unit having a primary amino group or a secondary amino group; and  
       said second polymer strand is characterized by a repeat unit having a tertiary amino group or a quaternary ammonium group.  
     
     
       24. The method of claim  23  wherein the second polymer strand is further characterized by a repeat unit having primary or secondary amino groups. 
     
     
       25. The method of claim  23  wherein the first polymer strand is selected from the group consisting of polyallylamine, polyvinylamine, poly(ethyleneimine), polydiallylamine, poly(N-alkylallylamine), and poly(N-alkylvinylamine). 
     
     
       26. The method of claim  25  wherein the first polymer strand is poly(N-methylallylamine) or poly(N-methylvinylamine). 
     
     
       27. The method of claim  24  wherein the second polymer strand is a copolymer characterized by a first repeat unit selected from the group consisting of N-alkyldiallylamine, N,N-dialkylallylamonium A-, N,N-dialkylallylamine, and N,N,N-trialkylallylammonium A-, wherein A- is an anion, and a second repeat unit selected from the group consisting of allylamine, vinylamine, diallylamine, N-alkylallylamine and N-alkylvinylamine. 
     
     
       28. The method of claim  27  wherein the second polymer strand is poly(N-alkyldiallylamine-co-diallylamine); poly(N,N-dialkyldiallylamonium-co-allylamine) A-; poly(N,N-dialkylallylamine-co-allylamine); poly(N,N-dialkylallylamine-co-N-alkylallylamine); poly(N,N,N-trialkylallylammonium-co-allylamine) A-; poly(N,N,N-trialkylallylammonium-co-N-alkylallylamine) A-; poly(N,N-dialkylvinylamine-co-vinylamine); poly(N,N-dialkylvinylamine-co-N-alkylvinylamine); poly(N,N,N-trialkylvinylammonium-co-vinylamine) A-; or poly(N,N,N-trialkylvinylammonium-co-N-alkylvinylamine) A-. 
     
     
       29. The method of claim  23  wherein the first polymer strand and the second polymer strand are connected by a bridging group selected from the group consisting of straight chain or branched, substituted or unsubstituted alkylene groups, diacylalkylene groups, diacylarene groups and alkylene bis(carbamoyl) groups. 
     
     
       30. The method of claim  29  wherein the bridging unit is selected from the group consisting of —(CH 2 ) n —, wherein n is an integer from about 2 to about 20; —CH 2 —CH(OH)—CH 2 —; —C(O)CH 2 CH 2 C(O)—; —CH 2 —CH(OH)—O—(CH 2 ) m —O—CH(OH) —CH 2 —, wherein m is 2 to about 4; —C(O)—(C 6 H 2 (COOH) 2 )—C(O)—; and —C(O)NH(CH 2 ) p NHC(O)—, wherein p is an integer from about 2 to about 20. 
     
     
       31. The method of claim  23  wherein the cross-linked polymer is produced by a method comprising the step of contacting a mixture comprising the first linear polymer and the second linear polymer with a crosslinking agent having two or more functional groups which react with amine groups to form a covalent bond, under conditions sufficient for cross-linking of the first linear polymer and the second linear polymer. 
     
     
       32. The method of claim  31  wherein the crosslinking agent is selected from the group consisting of epihalohydrin, succinyl dichloride, butanedioldiglycidyl ether, ethanedioldiglycidyl ether, pyromellitic dianhydride, dihaloalkanes and a,w-alkylene diisocyanatcs. 
     
     
       33. The method of claim  1  wherein the pathogenic toxin is produced by one or more bacteria. 
     
     
       34. The method of claim  33  wherein the one or more bacteria is selected from the group consisting of  E. coli  or  C. difficile.    
     
     
       35. The method of claim  1  wherein the pathogenic toxin is produced by one or more viruses. 
     
     
       36. The method of claim  1  wherein the pathogenic toxin is produced by one or more protozoa. 
     
     
       37. The method of claim  1  wherein the pathogenic toxin is produced by one or more fungus. 
     
     
       38. A method for inhibiting a pathogenic toxin in a mammal, comprising the step of orally administering to the mammal a therapeutically effective amount of a polymer comprising a plurality of pendant cationic groups each connected to the polymer backbone by an aliphatic spacer group. 
     
     
       39. The method of claim  38  wherein the mammal is a human. 
     
     
       40. The method of claim  38  wherein the polymer further comprises a hydrophobic group. 
     
     
       41. The method of claim  38  wherein the cationic group is an amino group or an ammonium group. 
     
     
       42. The method of claim  1  wherein R 1  is an ammonioalkyl group of the formula                    
       wherein R 4 , R 5  and R 6  are each, independently, a hydrogen atom, a C 1 -C 24  alkyl group; n is an integer from 2 to about 20; or —N + (R 4 )(R 5 )(R 6 ) is a heteroaryl group; and A −  is an anion; or a free base thereof. 
     
     
       43. The method of claim  1  wherein the polymer is a homopolymer. 
     
     
       44. The method of claim  1  wherein the polymer is a copolymer. 
     
     
       45. The method of claim  44  wherein the copolymer is a terpolymer. 
     
     
       46. The method of claim  44  wherein the polymer further comprises a hydrophobic monomer. 
     
     
       47. The method of claim  46  wherein the polymer further comprises a neutral hydrophilic monomer. 
     
     
       48. A method of inhibiting a pathogenic toxin in a mammal, comprising the step of orally administering to the mammal a therapeutically effective amount of a polymer comprising a monomer of Formula II,                    
       wherein R 7  and R 8  are each, independently, a hydrogen atom, a normal or branched, substituted or unsubstituted C 1 -C 24 -alkyl group, an aryl group or an arylalkyl group; and n is an integer from 2 to about 10; or a free base thereof. 
     
     
       49. The method of claim  48  wherein R 7  is an ammonioalkyl group of the formula                    
       wherein R 4 , R 5  and R 6  are each, independently, a hydrogen atom, a C 1 -C 24  alkyl group or an aryl group; or —N + R 4 R 5 R 6  is a heteroaryl group; n is an integer from 2 to about 20; and A − is a pharmaceutically acceptable anion; or a free base thereof.